Evaluating the Effect of Telomere Length on Oral and Oropharyngeal Cancer Risk Using Mendelian Randomization.

INTRODUCTION: The aim of this study was to explore the causal relationship between telomere length and Oral and oropharyngeal cancers by using Mendelian randomization (MR) analysis. METHODS: We carried out a 2-sample MR to examine the causal association between telomere length and Oral and oropharyngeal cancers. Two large genome-wide association studies (GWAS) were employed to identify single nucleotide polymorphisms (SNPs) as instrumental variables through statistical and biological approaches. The data on SNP-oral and oropharyngeal cancer risk factor associations were sourced from various consortia/UK Biobank. The inverse variance weighted (IVW) method was employed as the primary approach for overall causal estimation in MR, with sensitivity analyses conducted to assess potential confounding by pleiotropy, heterogeneity, and the leave-one-out analysis. RESULTS: The statistically driven approach indicates limited evidence of a genetically causal effect of telomere length on the risk of oral cavity cancer (OR = 0.999, 95% CI 0.998-1.000, P = .100), oropharyngeal cancer (OR = 0.999, 95% CI 0.998-1.001, P = .650), combined oral and oropharyngeal cancer (OR = 0.999, 95% CI 0.998-1.000, P = .119) in Europeans. The biologically driven approach demonstrated consistent causal effects across all MR methods, thereby further strengthening the reliability of the results. Moreover, the MR-Egger (Q [df] 170.816 [130], P = .009) and inverse variance weighted methods (Q [df] 171.656 [131], P = .010) identified considerable heterogeneity among instrumental variable estimates in Oral cavity cancer, and no evidence of horizontal pleiotropy was detected. CONCLUSIONS: No significant causal associations between telomere length and Oral and oropharyngeal cancers were found in this study.

DSS1 restrains BRCA2's engagement with dsDNA for homologous recombination, replication fork protection, and R-loop homeostasis.

DSS1, essential for BRCA2-RAD51 dependent homologous recombination (HR), associates with the helical domain (HD) and OB fold 1 (OB1) of the BRCA2 DSS1/DNA-binding domain (DBD) which is frequently targeted by cancer-associated pathogenic variants. Herein, we reveal robust ss/dsDNA binding abilities in HD-OB1 subdomains and find that DSS1 shuts down HD-OB1's DNA binding to enable ssDNA targeting of the BRCA2-RAD51 complex. We show that C-terminal helix mutations of DSS1, including the cancer-associated R57Q mutation, disrupt this DSS1 regulation and permit dsDNA binding of HD-OB1/BRCA2-DBD. Importantly, these DSS1 mutations impair BRCA2/RAD51 ssDNA loading and focus formation and cause decreased HR efficiency, destabilization of stalled forks and R-loop accumulation, and hypersensitize cells to DNA-damaging agents. We propose that DSS1 restrains the intrinsic dsDNA binding of BRCA2-DBD to ensure BRCA2/RAD51 targeting to ssDNA, thereby promoting optimal execution of HR, and potentially replication fork protection and R-loop suppression.

A dual-center study: can ultrasound radiomics differentiate type I and type II epithelial ovarian cancer patients with normal CA125 levels?

OBJECTIVE: CA125 is recommended by many countries as the primary screening test for ovarian cancer. But there are patients with ovarian cancer having normal CA125. We hope to identify the types of EOC with normal CA125 levels better by building a refined model based on the ultrasound radiomics, thus providing precise medical treatment for patients. METHODS: We included 58 patients with EOC with normal CA125 from 2 centres, who were confirmed by preoperative ultrasound and pathology. We extracted 1130 radiomics features based on the tumour's region of interest from the most typical ultrasound image of each patient. We selected radiomics and clinical features by LASSO and logistic regression to construct Rad-score and clinical models, respectively. Receiver operating characteristic curves judged their test efficacy. On the basis of the combined model, we developed a nomogram. RESULTS: Area under the curves (AUCs) of 0.93 and 0.83 were achieved in both the training and test groups for the combined model. There were similar AUCs between the Rad-score and clinical models of 0.82 and 0.80, respectively. By analysing the calibration curves, it was determined that the nomogram matched actual observations in the training cohort. CONCLUSION: Ultrasound radiomics can differentiate type I and type II EOC with normal CA125 levels. ADVANCES IN KNOWLEDGE: This study is the first to focus on EOC cases with normal level of CA125. The subset of patients constituting 20% of the disease population may require more refined radiomics models.

Effect of different approaches of direct radiation on the surface structure and caries susceptibility of enamel.

It is not clear whether different radiation methods have different effects on enamel. The purpose of this study was to compare the effects of single and fractionated radiation on enamel and caries susceptibility and to provide an experimental basis for further study of radiation­related caries. Thirty-six caries-free human third molars were collected and randomly divided into three groups (n = 12). Group1 (control group) was not exposed to radiation. Group 2 received single radiation with a cumulative dose of 70 Gy. Group 3 underwent fractionated radiation, receiving 2 Gy/day for 5 days followed by a 2-day rest period, for a total of 7 weeks with a cumulative dose of 70 Gy. Changes in microhardness, roughness, surface morphology, bacterial adhesion and ability of acid resistance of each group were tested. Scanning electron microscope revealed that the enamel surface in both radiation groups exhibited unevenness and cracks. Compared with the control group, microhardness and acid resistance of enamel decreased, while roughness and bacterial adhesion increased in both the single radiation and fractionated radiation groups. Compared with the single radiation group, the enamel surface microhardness and acid resistance decreased in the fractionated radiation group, while roughness and bacterial adhesion increased. Both single radiation and fractionated radiation resulting in changes in the physical and biological properties of enamel, with these changes being more pronounced in the fractionated radiation group. Therefore, fractionated radiation is recommended as a more suitable method for constructing a radiation­related caries model in vitro.

AI-based automated segmentation for ovarian/adnexal masses and their internal components on ultrasound imaging.

Purpose: Segmentation of ovarian/adnexal masses from surrounding tissue on ultrasound images is a challenging task. The separation of masses into different components may also be important for radiomic feature extraction. Our study aimed to develop an artificial intelligence-based automatic segmentation method for transvaginal ultrasound images that (1) outlines the exterior boundary of adnexal masses and (2) separates internal components. Approach: A retrospective ultrasound imaging database of adnexal masses was reviewed for exclusion criteria at the patient, mass, and image levels, with one image per mass. The resulting 54 adnexal masses (36 benign/18 malignant) from 53 patients were separated by patient into training (26 benign/12 malignant) and independent test (10 benign/6 malignant) sets. U-net segmentation performance on test images compared to expert detailed outlines was measured using the Dice similarity coefficient (DSC) and the ratio of the Hausdorff distance to the effective diameter of the outline ( R HD - D ) for each mass. Subsequently, in discovery mode, a two-level fuzzy c-means (FCM) unsupervised clustering approach was used to separate the pixels within masses belonging to hypoechoic or hyperechoic components. Results: The DSC (median [95% confidence interval]) was 0.91 [0.78, 0.96], and R HD - D was 0.04 [0.01, 0.12], indicating strong agreement with expert outlines. Clinical review of the internal separation of masses into echogenic components demonstrated a strong association with mass characteristics. Conclusion: A combined U-net and FCM algorithm for automatic segmentation of adnexal masses and their internal components achieved excellent results compared with expert outlines and review, supporting future radiomic feature-based classification of the masses by components.

Associations of overweight/obesity with patient-reported outcome measures after oblique lumbar interbody fusion.

Background: Oblique lateral interbody fusion (OLIF) combined with transpedicular screw fixation has been practiced for degenerative spinal diseases of elderly patients for years. However, overweight patients have been shown to have longer operative times and more complications from surgery. The effect on clinical outcome is still uncertified. The objective of this study was to determine is overweight a risk factor to clinical outcome of OLIF combined with transpedicular screw fixation technique. Material and methods: A retrospective study in patients submitted to OLIF combined with transpedicular screw fixation from January 2018 to August 2019 was conducted. VAS score, ODI score and EQ5D were measured before the operation and one year after the operation. Results: A total of 111 patients were included with 48 patients in the non-obese group and 55 patients in the overweight/obese group. There was no significant difference between the two groups in gender, age, smoking history, hypertension, chronic kidney disease and diabetes mellitus. Overweight/obese group has higher BMI (28.4 vs. 22.7, p < 0.001) than non-obese group. There was no difference between the two groups in pre-operative VAS score, ODI score and EQ5D score. However, the healthy weight group improved much more than the overweight score in VAS score, ODI score and EQ5D score. Conclusion: The overweight/obese patient group had clinical outcomes worse than the non-obese group in terms of pain relief and life functions.

Transcription-coupled DNA repair protects genome stability upon oxidative stress-derived DNA strand breaks.

Elevated oxidative stress, which threatens genome stability, has been detected in almost all types of cancers. Cells employ various DNA repair pathways to cope with DNA damage induced by oxidative stress. Recently, a lot of studies have provided insights into DNA damage response upon oxidative stress, specifically in the context of transcriptionally active genomes. Here, we summarize recent studies to help understand how the transcription is regulated upon DNA double strand breaks (DSB) and how DNA repair pathways are selectively activated at the damage sites coupling with transcription. The role of RNA molecules, especially R-loops and RNA modifications during the DNA repair process, is critical for protecting genome stability. This review provides an update on how cells protect transcribed genome loci via transcription-coupled repair pathways.

Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair.

Drugs targeting the DNA damage response (DDR) are widely used in cancer therapy, but resistance to these drugs remains a major clinical challenge. Here, we show that SYCP2, a meiotic protein in the synaptonemal complex, is aberrantly and commonly expressed in breast and ovarian cancers and associated with broad resistance to DDR drugs. Mechanistically, SYCP2 enhances the repair of DNA double-strand breaks (DSBs) through transcription-coupled homologous recombination (TC-HR). SYCP2 promotes R-loop formation at DSBs and facilitates RAD51 recruitment independently of BRCA1. SYCP2 loss impairs RAD51 localization, reduces TC-HR, and renders tumors sensitive to PARP and topoisomerase I (TOP1) inhibitors. Furthermore, our studies of two clinical cohorts find that SYCP2 overexpression correlates with breast cancer resistance to antibody-conjugated TOP1 inhibitor and ovarian cancer resistance to platinum treatment. Collectively, our data suggest that SYCP2 confers cancer cell resistance to DNA-damaging agents by stimulating R-loop-mediated DSB repair, offering opportunities to improve DDR therapy.

The FANCI/FANCD2 complex links DNA damage response to R-loop regulation through SRSF1-mediated mRNA export.

Fanconi anemia (FA) is characterized by congenital abnormalities, bone marrow failure, and cancer susceptibility. The central FA protein complex FANCI/FANCD2 (ID2) is activated by monoubiquitination and recruits DNA repair proteins for interstrand crosslink (ICL) repair and replication fork protection. Defects in the FA pathway lead to R-loop accumulation, which contributes to genomic instability. Here, we report that the splicing factor SRSF1 and FANCD2 interact physically and act together to suppress R-loop formation via mRNA export regulation. We show that SRSF1 stimulates FANCD2 monoubiquitination in an RNA-dependent fashion. In turn, FANCD2 monoubiquitination proves crucial for the assembly of the SRSF1-NXF1 nuclear export complex and mRNA export. Importantly, several SRSF1 cancer-associated mutants fail to interact with FANCD2, leading to inefficient FANCD2 monoubiquitination, decreased mRNA export, and R-loop accumulation. We propose a model wherein SRSF1 and FANCD2 interaction links DNA damage response to the avoidance of pathogenic R-loops via regulation of mRNA export.

Revisiting Aurora Kinase B: A promising therapeutic target for cancer therapy.

Cancer continues to be a major health concern globally, although the advent of targeted therapy has revolutionized treatment options. Aurora Kinase B is a serine-threonine kinase that has been explored as an oncology therapeutic target for more than two decades. Aurora Kinase B inhibitors show promising biological results in in-vitro and in-vivo experiments. However, there are no inhibitors approved yet for clinical use, primarily because of the side effects associated with Aurora B inhibitors. Several studies demonstrate that Aurora B inhibitors show excellent synergy with various chemotherapeutic agents, radiation therapy, and targeted therapies. This makes it an excellent choice as an adjuvant therapy to first-line therapies, which greatly improves the therapeutic window and side effect profile. Recent studies indicate the role of Aurora B in some deadly cancers with limited therapeutic options, like triple-negative breast cancer and glioblastoma. Herein, we review the latest developments in Aurora Kinase B targeted research, with emphasis on its potential as an adjuvant therapy and its role in some of the most difficult-to-treat cancers.

DFT-Based Study of the Structure, Stability, and Spectral and Optical Properties of Gas-Phase NbMgn (n = 2-12) Clusters.

Gas-phase NbMgn (n = 2-12) clusters were fully searched by CALYPSO software, and then the low-energy isomers were further optimized and calculated under DFT. It is shown that the three lowest energy isomers of NbMgn (n = 3-12) at each size are grown from two seed structures, i.e., tetrahedral and pentahedral structures, and the transition size occurs at the NbMg8 cluster. Interestingly, the relative stability calculations of the NbMg8 cluster ground-state isomer stand out under the examination of several parameters' calculations. The charge-transfer properties of the clusters of the ground-state isomers of various sizes had been comprehensively investigated. In order to be able to provide data guidance for future experimental probing of these ground-state clusters, this work also predicted infrared and Raman spectra at the same level of theoretical calculations. The results show that the multipeak nature of the IR and Raman spectra predicts that it is difficult to distinguish them directly. Finally, the optical properties of these clusters were investigated by calculating the static linear, second-order nonlinear, and third-order nonlinear coefficients. Importantly and interestingly, the NbMg8 cluster was shown to have superior nonlinear optical characteristics to all other clusters; thus, it is a powerful candidate for a potentially ultrasensitive nonlinear optical response device for some special purpose.

ATR inhibition induces synthetic lethality in mismatch repair-deficient cells and augments immunotherapy.

The mismatch repair (MMR) deficiency of cancer cells drives mutagenesis and offers a useful biomarker for immunotherapy. However, many MMR-deficient (MMR-d) tumors do not respond to immunotherapy, highlighting the need for alternative approaches to target MMR-d cancer cells. Here, we show that inhibition of the ATR kinase preferentially kills MMR-d cancer cells. Mechanistically, ATR inhibitor (ATRi) imposes synthetic lethality on MMR-d cells by inducing DNA damage in a replication- and MUS81 nuclease-dependent manner. The DNA damage induced by ATRi is colocalized with both MSH2 and PCNA, suggesting that it arises from DNA structures recognized by MMR proteins during replication. In syngeneic mouse models, ATRi effectively reduces the growth of MMR-d tumors. Interestingly, the antitumor effects of ATRi are partially due to CD8+ T cells. In MMR-d cells, ATRi stimulates the accumulation of nascent DNA fragments in the cytoplasm, activating the cGAS-mediated interferon response. The combination of ATRi and anti-PD-1 antibody reduces the growth of MMR-d tumors more efficiently than ATRi or anti-PD-1 alone, showing the ability of ATRi to augment the immunotherapy of MMR-d tumors. Thus, ATRi selectively targets MMR-d tumor cells by inducing synthetic lethality and enhancing antitumor immunity, providing a promising strategy to complement and augment MMR deficiency-guided immunotherapy.

The RNA m5C modification in R-loops as an off switch of Alt-NHEJ.

The roles of R-loops and RNA modifications in homologous recombination (HR) and other DNA double-stranded break (DSB) repair pathways remain poorly understood. Here, we find that DNA damage-induced RNA methyl-5-cytosine (m5C) modification in R-loops plays a crucial role to regulate PARP1-mediated poly ADP-ribosylation (PARylation) and the choice of DSB repair pathways at sites of R-loops. Through bisulfite sequencing, we discover that the methyltransferase TRDMT1 preferentially generates m5C after DNA damage in R-loops across the genome. In the absence of m5C, R-loops activate PARP1-mediated PARylation both in vitro and in cells. Concurrently, m5C promotes transcription-coupled HR (TC-HR) while suppressing PARP1-dependent alternative non-homologous end joining (Alt-NHEJ), favoring TC-HR over Alt-NHEJ in transcribed regions as the preferred repair pathway. Importantly, simultaneous disruption of both TC-HR and Alt-NHEJ with TRDMT1 and PARP or Polymerase θ inhibitors prevents alternative DSB repair and exhibits synergistic cytotoxic effects on cancer cells, suggesting an effective strategy to exploit genomic instability in cancer therapy.

Clinical Evaluation of Cystic Renal Masses With Bosniak Classification by Contrast-Enhanced Ultrasound and Contrast-Enhanced Computer Tomography.

OBJECTIVES: The study aims to compare retrospectively three clinically applied methods for the diagnostic performance of cystic renal masses (CRMs) by contrast-enhanced ultrasound (CEUS) and contrast-enhanced computer tomography (CECT) with Bosniak classification system. METHODS: A total of 52 cases of Bosniak II-IV CRMs in 49 consecutive patients were diagnosed from January 2013 to July 2022 and their data were analyzed. All patients had been subjected to CEUS and CECT simultaneously. Pathological diagnoses and masses stability were used as standard references to determine whether lesions were malignant or benign. Then 49 CRMs only with pathologic results were classified into group 1 and 2. RESULTS: A total of 52 CRMs in 49 enrolled patients were classified into 8 category II, 16 category IIF, 15 category III, and 13 category IV by CEUS (EFSUMB 2020), 10 category II, 13 category IIF, 16 category III, and 13 category IV by CEUS (V2019), while 15 category II, 9 category IIF, 13 category III, and 15 category IV by CECT (V2019). Pathological results and masses stability longer than 5 years follow-up performed substantially for CEUS (EFSUMB 2020), CEUS (V2019), and CECT (V2019) (kappa values were 0.696, 0.735, and 0.696, respectively). Among 49 pathologic approving CRMs, wall/septation thickness ≥4 mm, wall/septation thickness, presence of enhancing nodule and the diameter were found to be statistically significant for malignancy. Twenty-two malignant masses were correctly diagnosed by CEUS (V2019), while 21 malignant masses were both correctly diagnosed by CEUS (EFSUMB 2020) and CECT (V2019), and 1 mass was misdiagnosed. CONCLUSIONS: Bosniak classification of EFSUMB 2020 version might be as accurate as version 2019 CEUS and version 2019 CECT in diagnosing CRMs, and CEUS is found to have an excellent safety profile in dealing with clinical works.

Radiomic and deep learning characterization of breast parenchyma on full field digital mammograms and specimen radiographs: a pilot study of a potential cancer field effect.

Purpose: In women with biopsy-proven breast cancer, histologically normal areas of the parenchyma have shown molecular similarity to the tumor, supporting a potential cancer field effect. The purpose of this work was to investigate relationships of human-engineered radiomic and deep learning features between regions across the breast in mammographic parenchymal patterns and specimen radiographs. Approach: This study included mammograms from 74 patients with at least 1 identified malignant tumor, of whom 32 also possessed intraoperative radiographs of mastectomy specimens. Mammograms were acquired with a Hologic system and specimen radiographs were acquired with a Fujifilm imaging system. All images were retrospectively collected under an Institutional Review Board-approved protocol. Regions of interest (ROI) of 128×128 pixels were selected from three regions: within the identified tumor, near to the tumor, and far from the tumor. Radiographic texture analysis was used to extract 45 radiomic features and transfer learning was used to extract 20 deep learning features in each region. Kendall's Tau-b and Pearson correlation tests were performed to assess relationships between features in each region. Results: Statistically significant correlations in select subgroups of features with tumor, near to the tumor, and far from the tumor ROI regions were identified in both mammograms and specimen radiographs. Intensity-based features were found to show significant correlations with ROI regions across both modalities. Conclusions: Results support our hypothesis of a potential cancer field effect, accessible radiographically, across tumor and non-tumor regions, thus indicating the potential for computerized analysis of mammographic parenchymal patterns to predict breast cancer risk.

Prognostic scoring system based on eosinophil- and basophil-related markers for predicting the prognosis of patients with stage II and stage III colorectal cancer: a retrospective cohort study.

Background: Systemic inflammation is associated with the prognosis of colorectal cancer (CRC). The current study aimed to construct a comprehensively inflammatory prognostic scoring system named risk score (RS) based on eosinophil- and basophil-related markers and assess its prognostic value in patients with stage II and stage III CRC. Patients and methods: A total of 3,986 patients were enrolled from January 2007 to December 2013. The last follow-up time was January 2019. They were randomly assigned to the training set and testing set in a 3:2 split ratio. Least absolute shrinkage and selection operator (LASSO)-Cox regression analysis was performed to select the optimal prognostic factors in the construction of RS. The Kaplan-Meier curve, time-dependent receiver operating characteristic (ROC), and Cox analysis were used to evaluate the association between RS and overall survival (OS). Results: In the training set, all inflammatory markers showed certain prognostic values. Based on LASSO-Cox analysis, nine markers were integrated to construct RS. The Kaplan-Meier curve showed that a higher RS (RS > 0) had a significantly worse prognosis (log-rank p< 0.0001). RS (>0) remained an independent prognostic factor for OS (hazard ratio (HR): 1.70, 95% confidence interval (CI), 1.43-2.03, p< 0.001). The prognostic value of RS was validated in the entire cohort. Time-dependent ROC analysis showed that RS had a stable prognostic effect throughout the follow-up times and could enhance the prognostic ability of the stage by combination. Nomogram was established based on RS and clinicopathological factors for predicting OS in the training set and validated in the testing set. The area under the curve (AUC) values of the 3-year OS in the training and testing sets were 0.748 and 0.720, respectively. The nomogram had a satisfactory predictive accuracy and had better clinical application value than the tumor stage alone. Conclusions: RS might be an independent prognostic factor for OS in patients with stage II and III CRC, which is helpful for risk stratification of patients. Additionally, the nomogram might be used for personalized prediction and might contribute to formulating a better clinical treatment plan.

[Taurine inhibits M2 polarization of macrophages by promoting mitophagy].

Objective To investigate the molecular mechanism of taurine regulating the polarization of M2 macrophages by mitophagy. Methods THP-1 cells were divided into four groups: M0 group (THP-1 cells were treated by 100 nmol/L phorbol myristate ester for 48 hours to polarize into M0), M2 group (THP-1 cells were induced to polarize into M2 macrophages by 20 ng/mL interferon-4 (IL-4) for 48 hours), M2 combined with taurine groups (added with 40 or 80 mmol/L taurine on the basis of M2 macrophages). The mRNA expression of mannose receptor C type 1(MRC-1), C-C motif chemokine ligand 22(CCL22) and dendritic cell-specific ICAM-3 grabbing non-integrin (CD209) in M2 macrophages were detected by quantitative real-time PCR. Mitochondrial and lysosome probes were used to detect the number of mitochondria and lysosomes by multifunction microplate reader and confocal laser scanning microscope. The level of mitochondrial membrane potential (MMP) was detected by JC-1 MMP assay kit. The expression of mitophagy-related proteins PTEN-induced putative kinase 1 (PINK1) and microtubule-associated protein 1 light chain 3 (LC3) were detected by Western blot analysis. Results Compared with M0 group, the expression of MRC-1, CCL22, CD209 and PINK1, the number of mitochondria and the level of MMP in M2 group were significantly increased, whereas the number of lysosomes and LC3II/LC3I ratio were decreased. Compared with M2 group, the expressions of MRC-1, CCL22 and CD209, the number of mitochondria and the level of MMP in M2 combined with taurine group dropped significantly while the number of lysosomes was found increased, and the protein expression of PINK1 and LC3II/LC3I ratio were also increased. Conclusions The polarization of M2 macrophages is regulated by taurine to prevent excessive polarization via reducing the level of MMP, improving the level of mitophagy, reducing the number of mitochondria, and inhibiting the mRNA expression of polarization markers in M2 macrophages.

Design, synthesis, and anticancer evaluation of arylurea derivatives as potent and selective type II irreversible covalent FGFR4 inhibitors.

Aberrant FGF19/FGFR4 signaling has been demonstrated to be an oncogenic driver of growth and survival in human hepatocellular carcinoma (HCC). At present, the development of FGFR4-specific drugs has become a hotspot in tumor-targeted therapy research. However, no selective FGFR4 inhibitors have been approved by FDA so far. Currently, most of the reported FGFR4 inhibitors that use a covalent targeting strategy to be selective are typical type I inhibitors with a single type. Here, based on Ponatinib, we designed and synthesized a series of arylurea derivatives as novel type II irreversible covalent inhibitors of FGFR4. Among them, the representative compound 6v exhibited an IC50 value of 74 nM against FGFR4 and antiproliferative potency of 0.25 µM and 0.22 µM against Huh7 and Hep3B cell lines. Western blotting results showed that compound 6v significantly inhibited the phosphorylation of FGFR4 and its downstream signaling factors AKT and ERK in a dose-dependent manner in Hep3B cell. These results showed that this series of compounds, as type II irreversible FGFR4 inhibitors, are worthy of further research and structural optimization.

The DACH1 gene is frequently deleted in prostate cancer, restrains prostatic intraepithelial neoplasia, decreases DNA damage repair, and predicts therapy responses.

Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. The DACH1 gene encodes a winged helix/Forkhead DNA-binding protein that competes for binding to FOXM1 sites. Herein, DACH1 gene deletion within the 13q21.31-q21.33 region occurs in up to 18% of human PCa and was associated with increased AR activity and poor prognosis. In prostate OncoMice, prostate-specific deletion of the Dach1 gene enhanced prostatic intraepithelial neoplasia (PIN), and was associated with increased TGFß activity and DNA damage. Reduced Dach1 increased DNA damage in response to genotoxic stresses. DACH1 was recruited to sites of DNA damage, augmenting recruitment of Ku70/Ku80. Reduced Dach1 expression was associated with increased homology directed repair and resistance to PARP inhibitors and TGFß kinase inhibitors. Reduced Dach1 expression may define a subclass of PCa that warrants specific therapies.

Temporal Machine Learning Analysis of Prior Mammograms for Breast Cancer Risk Prediction.

The identification of women at risk for sporadic breast cancer remains a clinical challenge. We hypothesize that the temporal analysis of annual screening mammograms, using a long short-term memory (LSTM) network, could accurately identify women at risk of future breast cancer. Women with an imaging abnormality, which had been biopsy-confirmed to be cancer or benign, who also had antecedent imaging available were included in this case-control study. Sequences of antecedent mammograms were retrospectively collected under HIPAA-approved guidelines. Radiomic and deep-learning-based features were extracted on regions of interest placed posterior to the nipple in antecedent images. These features were input to LSTM recurrent networks to classify whether the future lesion would be malignant or benign. Classification performance was assessed using all available antecedent time-points and using a single antecedent time-point in the task of lesion classification. Classifiers incorporating multiple time-points with LSTM, based either on deep-learning-extracted features or on radiomic features, tended to perform statistically better than chance, whereas those using only a single time-point failed to show improved performance compared to chance, as judged by area under the receiver operating characteristic curves (AUC: 0.63 ± 0.05, 0.65 ± 0.05, 0.52 ± 0.06 and 0.54 ± 0.06, respectively). Lastly, similar classification performance was observed when using features extracted from the affected versus the contralateral breast in predicting future unilateral malignancy (AUC: 0.63 ± 0.05 vs. 0.59 ± 0.06 for deep-learning-extracted features; 0.65 ± 0.05 vs. 0.62 ± 0.06 for radiomic features). The results of this study suggest that the incorporation of temporal information into radiomic analyses may improve the overall classification performance through LSTM, as demonstrated by the improved discrimination of future lesions as malignant or benign. Further, our data suggest that a potential field effect, changes in the breast extending beyond the lesion itself, is present in both the affected and contralateral breasts in antecedent imaging, and, thus, the evaluation of either breast might inform on the future risk of breast cancer.